Summary: This proposal examines the regulatory effects of microbe- and host-derived activation factors on the innate immune system in an experimental model of human disease. Human Sleeping Sickness is a fatal disease characterized by extensive functional, histological and pathological changes in the lymphoid tissues of Trypanosoma spp. infected hosts. Among these changes is an increase in the numbers and activation state of cells of the mononuclear phagocyte system. Macrophage activation during infection occurs in response to molecules released by the parasite as well as to IFN-y produced by T cells in response to parasite antigens. These activation events occur episodically throughout infection, associated with waves of parasite growth and immune destruction; thus trypanosome infections represent a natural model in which the macrophage component of the innate immune system is exposed in a recurrent manner to microbial factors ("danger" signals) and to host cytokines. We present evidence that the two factors produce distinct patterns of macrophage activation during infection, and that the balance or interaction of the different activation signals may determine the progression of disease and outcome of infection. Since the macrophage activation response is based on distinct membrane-associated signaling events, and since macrophage activation is intimately linked to host protection, an effort to understand the molecular basis for macrophage activation is clearly an important scientific step towards understanding the host-parasite relationship and the concept of macrophage co-activation during microbial infection. Therefore, this proposal examines basic elements of cell biology and molecular signaling to dissect the macrophage activation response in African trypanosomiasis. The ultimate goal is to uncover novel regulatory mechanisms associated with macrophage activation that can be exploited to provide greater resistance to disease.